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bioRxiv2021

Development of a novel, pan-variant aerosol intervention for COVID-19

To develop a universal strategy to block SARS-CoV-2 cellular entry and infection represents a central aim for effective COVID-19 therapy. The growing impact of emerging variants of concern increases the urgency for development of effective interventions. Since ACE2 is the critical SARS-CoV-2 receptor and all tested variants bind to ACE2, some even at much increased affinity (see accompanying paper), we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways. Here we show that intranasal administration of APN01 in a mouse model of SARS-CoV-2 infection dramatically reduced weight loss and prevented animal death. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization. We report successful aerosolization for APN01, retaining viral binding as well as catalytic RAS activity. Dose range-finding and IND-enabling repeat-dose aerosol toxicology testing were conducted in dogs. Twice daily aerosol administration for two weeks at the maximum feasible concentration revealed no notable toxicities. Based on these results, a Phase I clinical trial in healthy volunteers can now be initiated, with subsequent Phase II testing in individuals with SARS-CoV-2 infection. This strategy could be used to develop a viable and rapidly actionable therapy to prevent and treat COVID-19, against all current and future SARS-CoV-2 variants. One Sentence SummaryPreclinical development and evaluation of aerosolized soluble recombinant human ACE2 (APN01) administered as a COVID-19 intervention is reported.

pharmacology and toxicology↗

bioRxiv2024

Cystobactamid off-target profiling reveals favorable safety, superoxide reduction, and SCARB1 inhibition in eukaryotes

Antimicrobial resistance (AMR) poses a fundamental global threat, necessitating new strategies for effective therapies. Cystobactamids (CYS), a class of antibacterial agents targeting bacterial gyrase and topoisomerase IV, represent a non-traditional chemical scaffold with broad-spectrum activity. For toxicological de-risking, we performed a comprehensive profiling on eukaryotic cells, focusing on cytotoxicity, genotoxicity, and mitochondrial toxicity, demonstrating cellular safety and superoxide scavenging properties. Studies in zebrafish embryos assessed developmental, cardiovascular, and hepatic toxicity, indicating a favorable in vivo safety profile. Metabolism studies revealed glucuronidation and amide bond hydrolysis as key pathways, whereby CYS metabolic stability substantially improved by cobicistat co-treatment. Affinity-based protein profiling identified the cholesterol- and HCV-receptor scavenger receptor class B member 1 (SCARB1) as a primary eukaryotic off-target protein, with cystobactamids shown to inhibit SCARB1s function, preventing hepatitis C virus pseudoparticle entry into cells. These findings suggest a high therapeutic potential for cystobactamids and highlight SCARB1 as a primary eukaryotic target.

pharmacology and toxicology↗

bioRxiv2022

Interactions between genes altered during cardiotoxicity and neurotoxicity in zebrafish revealed using induced network modules analysis

Zebrafish has become a prominent model organism to study toxicology due to its genomic similarity to humans, optical clarity, well defined developmental stages, short generation time and cost-effective maintenance. It also provides a shorter time frame for in vivo toxicology evaluation compared to mammalian experimental systems. As manufacturing processes and development of new synthetic compounds increase to keep pace with the expanding global demand, environmental health and the effects of toxicant exposure are emerging as critical public health concerns. Owing to this, in this study, we analyzed the impact of such chemical induced toxicity in zebrafish. We first searched the literature comprehensively for genes that were modulated during neurotoxicity and cardiotoxicity in zebrafish and then studied the interactions between those genes using induced network modules analysis of the database ConsensusPathDB. The induced network modules analysis helps to study gene interactions through various types of interactions like gene regulatory, biochemical, genetic and protein interactions. A constant communication between the heart and the brain is an important physiological phenomenon. Therefore, we also analyzed the interactions among genes that are modulated simultaneously during cardiotoxicity and neurotoxicity. This study has led us to identify some potential predictive biomarkers for neurotoxicity and cardiotoxicity in zebrafish.

pharmacology and toxicology↗

bioRxiv2025

An evaluation of genotoxicity and 90-day repeated-dose toxicity in rats of a Dracocephalum moldavica powdered extract

The safety of a powdered extract of Dracocephalum moldavica (Dracobelle Nu sd) was examined through a battery of in vitro and in vivo toxicological studies including a bacterial reverse mutation test, an in vivo mammalian micronucleus assay in male NMRI mice, and a subchronic toxicity study in Han:Wist rats. No mutagenic activity was observed in any of the tested bacterial strains with or without metabolic activation in the reverse mutation test, and no evidence of clastogenic or aneugenic activity was observed in the in vivo mouse micronucleus test. In the 90-day repeated dose oral toxicity study conducted in 80 (40 male/40 female) rats at dose levels of 0 (control), 250, 500, and 1000 mg/kg bw/day, no treatment related mortality or clinical signs of toxicity were observed, and no significant adverse effects attributable to the test item were found in any of the examined parameters in accordance with the OECD guidelines. The No Observed Adverse Effect Level (NOAEL) was determined to be 1000 mg/kg bw/day in male and female rats, the highest dose tested.

pharmacology and toxicology↗

bioRxiv2026

DEDuCT 3.0: An enhanced and expanded FAIR-compliant resource and toxicology knowledge graph for endocrine disrupting chemicals

Endocrine disrupting chemicals (EDCs) are of particular regulatory and research interest due to the increasing incidence of endocrine-related disorders, such as declining fertility rates and reproductive health problems. The Database of Endocrine Disrupting Chemicals and their Toxicity Profiles (DEDuCT) has gained importance in both academic and regulatory settings by systematically curating data from published literature to characterize these chemicals. Given the growing body of EDC literature, this study aimed to consolidate the latest research and update this critical database. First, more than 14000 research articles were screened through an extensive four-stage manual process, and integrated with the earlier version to create the updated DEDuCTv3.0, comprising 1043 unique EDCs and 796 unique endocrine-related endpoints curated from 3269 published articles. Thereafter, human- and rodent-specific biological endpoint data including interacting genes/proteins, phenotypes, diseases, and adverse outcome pathways (AOPs) were curated from toxicology-relevant databases and systematically integrated with DEDuCTv3.0 to construct a large-scale toxicology knowledge graph for EDCs, termed DEDuCT-KG. DEDuCT-KG was then hosted on a Neo4j database and made easily accessible through a novel interactive user interface. The utility of DEDuCT-KG was demonstrated by exploring potential mechanisms of action associated with obesogenic EDCs within DEDuCTv3.0. Furthermore, the constructed EDC-AOP network, linking 949 EDCs to 381 AOPs within AOP-Wiki, revealed diverse toxicity mechanisms associated with EDCs. Integration with consumer product database and regulatory chemical lists showed that some of these EDCs are present in food contact materials, personal care products, and daily use items, highlighting potential exposure pathways. Overall, all data compiled in this study have been integrated into the DEDuCT webserver, which has been further enhanced to align with FAIR principles. In sum, this study provides a much-needed update to DEDuCT and offers a single point of access to EDC-relevant data to accelerate research and regulation of EDCs.

pharmacology and toxicology↗

bioRxiv2020

First-described recently discovered non-toxic vegetal-derived furocoumarin preclinical efficacy against SARS-CoV-2: a promising antiviral herbal drug.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiology of coronavirus disease 2019 (COVID19) pandemic. ICEP4 purified compound (ICEP4) is a recently discovered furocoumarin-related purified compound derived from the roots and seeds of Angelica archangelica (herbal drug). ICEP4-related herbal preparations have been extensively used as active herbal ingredients in traditional medicine treatments in several European countries. Extraction method of patent pending ICEP4 (patent application no. GB2017123.7) has previously shown strong manufacturing robustness, long-lasting stability, and repeated chemical consistency. Here we show that ICEP4 presents a significant in vitro cytoprotective effect in highly virulent-SARS-CoV-2 challenged Vero E6 cellular cultures, using doses of 34.5 and 69 M. No dose-related ICEP4 toxicity was observed in Vero E6 cells, M0 macrophages, B, CD4+ T and CD8+ T lymphocytes, Natural Killer (NK) or Natural Killer T (NKT) cells. No dose-related ICEP4 inflammatory response was observed in M0 macrophages quantified by IL6 and TNF release in cell supernatant. No decrease in survival rate was observed after either 24 hr acute or 21-day chronic exposure in in vivo toxicity studies performed in C. elegans. Therefore, ICEP4 toxicological profile has demonstrated marked differences compared to others vegetal furocoumarins. Successful ICEP4 doses against SARS-CoV-2-challenged cells are within the maximum threshold of toxicity concern (TTC) of furocoumarins as herbal preparation, stated by European Medicines Agency (EMA). The characteristic chemical compounding of ICEP4, along with its safe TTC, allow us to assume that the first-observation of a natural antiviral compound has occurred. The potential druggability of a new synthetic ICEP4-related compound remains to be elucidated. However, well-established historical use of ICEP4-related compounds as herbal preparations may point towards an already-safe, widely extended remedy, which may be ready-to-go for large-scale clinical trials under the EMA emergency regulatory pathway. To the best of the authors knowledge, ICEP4-related herbal drug can be postulated as a promising therapeutic treatment for COVID19.

pharmacology and toxicology↗

bioRxiv2023

Safety Assessment of a Standardized Polyherbal Formulation (Glubloc™): Acute Toxicity Study and 28-Day Repeated Dose Toxicological Studies

The standardized extract of Morus alba and Malus domestica Peel is widely recognized as a dietary supplement with potential benefits for blood sugar management, cholesterol reduction, and weight management. This study aimed to evaluate the general toxicity of the extract. Toxicity studies were conducted by OECD guidelines 425 and 407 and Schedule Y of the Drugs and Cosmetics Act, which mandates the use of two species for such studies. A single dose of GlublocTM at a concentration of 2000 mg/kg body weight was administered to Sprague Dawley rats and Albino mice, and no fatalities were reported, indicating good tolerability. Additionally, repeated oral administration of GlublocTM to rats and rabbits for a maximum duration of 28 days, at doses up to 414.16 mg/kg body weight per day in rats and 207.08 mg/kg body weight per day in rabbits, did not result in significant changes in medical assessments, ocular evaluations, weight gains, feeding behavior, or pathological findings compared to the control group. Overall, this study suggests that GlublocTM is well-tolerated without inducing any toxicity. The extracts No-Observed-Adverse-Effect Level (NOAEL) is considered to be 414.16 mg/kg per day when administered repeatedly for 28 days in rats and 207.08 mg/kg in rabbits.

pharmacology and toxicology↗

bioRxiv2025

Advanced Cardiac Organoid Model for Studying Doxorubicin-Induced Cardiotoxicity

Cardiac organoids provide an in vitro platform for studying heart disease mechanisms and drug responses. However, a major limitation is the immaturity of cardiomyocytes, restricting their ability to mimic adult cardiac physiology. Additionally, the inadequacy of commonly used extracellular matrices (ECM), which fail to replicate the biochemical and mechanical properties of natural heart tissue, poses significant challenges. Consequently, structural integrity in cardiac organoids is impaired. Moreover, scalability remains an obstacle, as conventional ECM substitutes hinder mass production of organoids for high-throughput toxicology screening. To overcome these challenges, we developed an advanced model promoting fibroblast-driven ECM self-secretion, enabling physiologically relevant tissue architecture and function. Using the ECM-free, mature cardiomyocyte-integrated organoid model, we investigated the cardiotoxicity of doxorubicin, a widely used chemotherapeutic agent known to impair cardiac function. Cardiomyocytes derived from induced pluripotent stem cells were characterized for maturity by immunostaining for cTNT and MYL2 alongside gene expression analysis. Organoids treated with doxorubicin showed reduced size and increased collagen deposition. These structural changes correlated with functional impairments, including decreased contraction rate and disrupted synchronous beating. In 2D culture, exposure to doxorubicin induced fibroblast activation, promoted endothelial-to-mesenchymal transition in endothelial cells, and triggered cytotoxic effects in cardiomyocytes. This study highlights the importance of ECM remodeling in advancing cardiac organoid models and demonstrates its potential for more accurate cardiotoxicity assessment. Addressing these limitations enhances the physiological relevance of cardiac organoid systems for drug safety assessment and cardiac disease modeling.

pharmacology and toxicology↗

bioRxiv2021

Cannabidiol pretreatment attenuates locomotor alterations and cytokine production in an autoimmune hepatitis model

Cannabidiol (CBD) is a major active component of the Cannabis plant (Cannabis Sativa L.), which unlike tetrahydrocannabinol (THC) is devoid of euphoria-inducing properties. Broadly, CBD has demonstrated anxiolytic-like, anti-inflammatory and immunomodulatory effects. Concanavalin A (ConA) is a lectin found in the jack bean (Canavalia ensiformis) and it has been associated with a variety of toxicological effects (upon them mitogenic, cytotoxic and hepatotoxic). Intravenous administration of ConA is widely used for the induction of a model to study autoimmune hepatitis (AIH) in mice and the injury is mainly driven by activation and uptake of T-cells in liver. The aim of the present study was to investigate the effects of CBD administration (20 mg/kg), on adult mice, on locomotor activity and inflammatory markers, upon induction of AIH by ConA administration (20 mg/kg) on Balb/C mice. Inflammatory analysis was assessed by determining the IL-2, IL-4, IL-10 and INF-{gamma} levels on plasma and sickness-like behavior assessed with open-field test. The results indicate that CBD pretreatment ameliorates impaired locomotor activity. IL-2, IL-4 and INF-{gamma} levels on plasma were increased after ConA intoxication (inflammation index) and were reduced when mice were pre-treated with CBD. The detected IL-10 levels were increased when CBD pretreated, suggesting a protective anti-inflammatory effect.

pharmacology and toxicology↗

bioRxiv2022

Toxicological Analysis of Poly-Lactide Co-Glycolide Microparticles, Chitosan Nanoparticles and Poly(Anhydride) Nanoparticles in Vero Cell

The present study was carried out to evaluate in-vitro toxicity associated with chitosan nanoparticles, poly(anhydride) nanoparticles and poly-lactide co-glycolide (PLG) microparticle in Vero cell line. The cytotoxicity of all three micro/nano-particles was assessed using different concentration. For each concentration, the confluent monolayer was treated for a period of 36-48 hours and studied for morphological alteration, live and death count etc. after the treatment. It was observed that the different concentrations of chitosan nanoparticles and Gantrez(R) nanoparticles did not have significant effect on the cell viability as evident from the non-significant difference between the OD540 of formazan product formed from MTT in treated and untreated cells. The concentration of chitosan nanoparticles and Gantrez(R) nanoparticles up to 1000 g/ml did not have any influence in cellular metabolic activities and viability. However, a reduction in the cellular viability and metabolic activities were observed when PLG microparticles were used at 1000 g/ml. At concentrations below 1000 g/ml, all the nanoparticles/microparticles were found to be safe in terms of cytotoxicity.

pharmacology and toxicology↗

bioRxiv2022

Reference compounds for characterizing cellular injury in high-content cellular morphology assays

Robust, generalizable approaches to identify compounds efficiently with undesirable mechanisms of action in complex cellular assays remain elusive. Such a process would be useful for hit triage during high-throughput screening and, ultimately, predictive toxicology during drug development. We generated cell painting and cellular health profiles for 218 prototypical cytotoxic and nuisance compounds in U-2 OS cells in a concentration-response format. A diversity of compounds causing cellular damage produced bioactive cell painting morphologies, including cytoskeletal poisons, genotoxins, nonspecific electrophiles, and redox-active compounds. Further, we show that lower quality lysine acetyltransferase inhibitors and nonspecific electrophiles can be distinguished from more selective counterparts. We propose that the purposeful inclusion of cytotoxic and nuisance reference compounds such as those profiled in this Resource will help with assay optimization and compound prioritization in complex cellular assays like cell painting.

pharmacology and toxicology↗

bioRxiv2026

Acute Toxicological Profile of Pharmaceutical-Grade Nicotinamide Riboside: A Route-Dependent Assessment Across Intravenous, Intramuscular, and Subcutaneous Administration

Nicotinamide riboside chloride (NR-Cl) has been studied predominantly by the oral route, while information regarding its toxicity following parenteral administration is limited. To characterize route-dependent acute toxicity and estimate median lethal doses (LD50), pharmaceutical-grade NR-Cl was evaluated following bolus intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration in female Sprague Dawley rats, in three independent studies. All studies were conducted using an adapted OECD Guideline 425 Up-and-Down procedure, modified for parenteral administration, in the absence of standardized route-specific OECD guidance. Animals received a single dose of NR-Cl via the respective administration route and were monitored for mortality, clinical signs, bodyweight changes, and gross pathological findings over a 14-day observation period. Following IM and SC administration, no mortalities were observed at doses up to 2000 mg/kg, and LD50 values for both routes were determined to be greater than 2000 mg/kg. In contrast, IV administration yielded an estimated LD50 of approximately 2000 mg/kg. These findings demonstrate that the acute toxicity of NR-Cl differs by route of administration and establish foundational safety benchmarks to support future research.

pharmacology and toxicology↗

bioRxiv2020

Statistical analysis of no observed effect concentrations or levels in eco-toxicological assays with overdispersed count endpoints

In (eco-)toxicological hazard characterization, the No Observed Adverse Effect Concentration or Level (NOAEC or NOAEL) approach is used and often required despite of its known limitations. For count data, statistical testing can be challenging, due to several confounding factors, such as zero inflation, low observation numbers, variance heterogeneity, over- or under-dispersion when applying the Poisson model or hierarchical experimental designs. As several tests are available for count data, we selected sixteen tests suitable for overdispersed counts and compared them in a simulation study. We assessed their performance considering data sets containing mixing distribution and over-dispersion with different observation numbers. It shows that there is no uniformly best approach because the assumed data conditions and assumptions are very different. However, the Dunnett-type procedure based on most likely transformation can be recommended, because of its size and power behavior, which is relatively better over most data conditions as compared to the available alternative test methods, and because it allows flexible modeling and effect sizes can be estimated by confidence intervals. Related R-code is provided for real data examples.

pharmacology and toxicology↗

bioRxiv2024

Mycotoxin candidalysin impairs epithelial barrier integrity and initiates inflammation in a gut-on-chip model

Candida albicans is an opportunistic pathogenic yeast commonly found in the gastrointestinal tract, vagina, and mouth of healthy humans. Under certain conditions, it can become invasive, causing mucosal or life-threatening systemic infections. One mechanism used by C.albicans to breach the epithelial barrier is the secretion of candidalysin, a cytolytic peptide toxin. Candidalysin damages epithelial membranes and activates the innate epithelial immune response, making it key to C.albicans pathogenicity and a promising therapeutic target. Although candidalysin mediates C. albicans translocation through intestinal layers, its impact on epithelial responses is not fully understood. This study aims to characterize this response and develop scalable, quantitative methodologies to assess candidalysins toxicological effects using gut-on-chip models. We used the OrganoPlate(R), a microfluidic platform to culture up to 64 perfused, membrane-free intestinal epithelial tubes. We exposed Caco-2 tubes to candidalysin and evaluated their response with trans-epithelial electrical resistance (TEER), protein detection, and immunostaining. We then validated our findings in a proof-of-concept experiment using human intestinal organoid tubules. Candidalysin impaired barrier integrity, as indicated by decreased TEER and increased permeability in a fluorescent dye assay. It also induced actin remodeling and DRAQ7 dye uptake, a marker of cell permeability. This disruption was associated with the release of LDH, cytokines, and the antimicrobial peptide LL37, suggesting cellular damage, inflammation, and antimicrobial activity. This study strengthens our understanding of candidalysins role in C. albicans pathogenesis and suggests new therapeutic strategies targeting this toxin. Moreover, the use of patient-derived organoids shows promise for capturing patient heterogeneity and developing personalized treatments. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/621017v4_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@dd8e35org.highwire.dtl.DTLVardef@1a33d18org.highwire.dtl.DTLVardef@113eorg.highwire.dtl.DTLVardef@6c2b9b_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Chitosan nanocapsules with Alstonia boonei extract modulate the immune system in Wistar rats

The development of biosynthetic methods for nanoparticles using plants presents an exciting opportunity to better utilize our rich and diverse medicinal flora. We are particularly interested in creating nanocapsules using Alstonia boonei, a Cameroonian plant known for its immunomodulatory properties. Chitosan nanocapsules were synthesized from the methanol/dichloromethane extract of the powdered stem bark of A. boonei after harvest and drying. The encapsulation of the secondary metabolites was achieved using the ionic gelation method, which involved the agitation of a chitosan solution, extract, and tripolyphosphate. Subsequently, the encapsulation efficiency was calculated. Infrared spectroscopy identified the various functional groups present in the nanocapsules. The acute toxicological profile of these chitosan nanocapsules at a limit dose of 2000 mg/kg, along with their immunomodulatory activities, was evaluated in Wistar rats. The immunomodulatory potential was assessed in dexamethasone-induced immunosuppressed rats by measuring total blood count, delayed-type hypersensitivity response, and hemagglutinating antibody titre between groups of animals after 14 days of treatment. The data collected on the synthesis and characterization confirmed the formation of nanocapsules. This was evidenced by infrared spectroscopy and an entrapment efficiency of 69%. Powder X-ray diffraction confirmed the presence of chitosan in the polymer material. SEM imaging further confirmed the formation of nanocapsules. The toxicological profile of these nanocapsules was found to be satisfactory. Administration of chitosan nanocapsules containing Al. boonei methanol/dichloromethane extracts at doses of 100 mg/kg, 200 mg/kg, and 500 mg/kg body weight significantly prevented dexamethasone-induced immunosuppression in rats. This was achieved by increasing the parameters of total blood count (hematocrit, mean corpuscular volume, platelets, lymphocytes, and granulocyte counts), hemagglutinating antibody titre values, and delayed type hypersensitivity response induced by chicken red blood cells. However, doses of 500 mg/kg of crude A. boonei extract and 500 mg/kg body weight of empty chitosan nanocapsules did not show this effect. The nanocapsules generated from the extracts of chitosan and A. boonei are responsible for immunostimulatory activity and possess therapeutic potentials for the prevention of depressed immune depressed conditions with satisfactory safety at acute dose.

pharmacology and toxicology↗

bioRxiv2021

Identifying the Link Between Chemical Exposures and Breast Cancer in African American Women via ToxCast High Throughput Screening Data

Among women, breast cancer is the most prevalent form of cancer worldwide and has the second highest mortality rate of any cancer in the United States. The breast cancer related death rate is 40% higher in African American women compared to European American women. The incidence of triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which there is no targeted therapy, is approximately three times higher in non-Hispanic Black women (NHBW) compared to non-Hispanic White women (NHWW). The drivers of these differences in breast cancer incidence and mortality are still poorly understood, and likely lie in an interaction between genetic and environmental factors. Here, we aimed to identify chemical exposures which may play a role in breast cancer disparities. Using chemical biomonitoring data from the National Health and Nutrition Examination Survey (NHANES) and biological activity data from the EPAs ToxCast program, we assessed the toxicological profiles of chemicals with higher biomarker concentrations in US NHBW. We conducted a literature search to identify a gene set of breast cancer targets included in ToxCast to analyze the response of prioritized chemicals in these assays. Forty-three chemical biomarkers are significantly higher in NHBW. Investigation of these chemicals in ToxCast resulted in a total of 32,683 assays for analysis, 5,172 of which contained nonzero values for the concentration at which the dose-response fitted model reaches the cutoff considered "active" and the scaled top value of dose response curve. Of these chemicals BPA, PFOS, and thiram are most comprehensively assayed. 2,5-dichlorophenol, 1,4-dichlorobenzene, and methyl and propyl parabens had higher biomarker concentrations in NHBW and moderate testing and activity in ToxCast. The distribution of active concentrations for these chemicals in ToxCast assays are comparable to biomarker concentrations in NHBW. Through this integrated analysis, we have identified that multiple chemicals, including thiram, propylparaben, and p,p DDE, with disproportionate exposures in NHBW, have breast cancer associated biological activity at human exposure relevant doses.

pharmacology and toxicology↗

bioRxiv2025

Characterizing common loss-of-function genes and their potential utility in assessing population variability and chemical susceptibility

Inter-individual and population variability in susceptibility to chemical exposures confounds determination of threshold exposure levels to protect the most vulnerable. Current risk assessment frameworks, in the absence of empiric chemical-specific data, generally recommend default or probabilistic adjustment factors to account for such variability. We present an experimental approach to incorporate common genetic variants potentially impacting population-level differences in toxicant susceptibility into human cell-based models for any cellular apical endpoint of interest. We focus on the genes with the most common aggregate loss-of-function (LoF) alleles in the gnomAD v3.0 data which we designated as the PopVarLoF set. Unexpectedly, enrichment analysis of these genes found significant overrepresentation of gene products playing important functional roles in toxicology. Interrogation of GWAS and PheWAS databases found that these genes are associated with diverse metabolic phenotypes consistent with the relevance of the PopVarLoF set in studying variability of toxicant response in human populations. We further characterized the PopVarLoF set by developing custom lentiviral CRISPR knockout libraries targeting the PopVarLoF genes to assess their functional essentiality in the HepG2/C3A cell line. Functional disruption of 14 of the PopVarLoF genes ([~]1 %) without toxicant exposure resulted in significant growth defects in this cell line, consistent with the majority of PopVarLoF gene products having non-essential roles. The development of human cell-based toxicity assays or other NAMs which include the empiric assessment of common genetic sources of population variability in susceptibility to chemical exposure could contribute to more robust risk assessment which protects vulnerable populations while reducing uncertainty. Impact statementWe characterize common loss of function genetic variants which could impact toxicant susceptibility and describe an approach to incorporate them into NAMs to enable empiric estimates of the contribution of genetic variability to diverse toxicity endpoints.

pharmacology and toxicology↗

bioRxiv2021

Circulating neurofilament light chain as a promising biomarker of AAV-induced dorsal root ganglia toxicity in nonclinical toxicology species

Adeno-associated virus (AAV)-induced dorsal root ganglia (DRG) toxicity has been observed in several nonclinical species, where lesions are characterized by neuronal degeneration/necrosis, nerve fiber degeneration, and mononuclear cell infiltration. As AAV vectors become an increasingly common platform for novel therapeutics, non-invasive biomarkers are needed to better characterize and manage the risk of DRG neurotoxicity in both nonclinical and clinical studies. Based on biological relevance, reagent availability, antibody cross-reactivity, DRG protein expression, and assay performance, neurofilament light chain (NF-L) emerged as a promising biomarker candidate. Dose- and time-dependent changes in NF-L were evaluated in male Wistar Han rats and cynomolgus monkeys following intravenous or intrathecal AAV injection, respectively. NF-L profiles were then compared against microscopic DRG lesions on Day 29 post-dosing. In animals exhibiting DRG toxicity, plasma/serum NF-L was strongly associated with the severity of neuronal degeneration/necrosis and nerve fiber degeneration, with elevations beginning as early as Day 8 in rats ([≥]5x1013 vg/kg) and Day 14 in monkeys ([≥]3.3x1013 vg/dose). Consistent with the unique positioning of DRGs outside the blood-brain barrier, NF-L in cerebrospinal fluid was only weakly associated with DRG findings. In summary, circulating NF-L is a promising biomarker of AAV-induced DRG toxicity in nonclinical species.

pharmacology and toxicology↗